AAC Accepts, published online ahead of print on 27 May 2008

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Antimicrob. Agents Chemother. doi:10.1128/AAC.00266-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Comparative study of the susceptibility of major epidemic clones of MRSA to oxacillin and to the new broad spectrum cephalosporin ceftobiprole

Marilyn Chung, Aude Antignac, Choonkeun Kim, and Alexander Tomasz^*

Laboratory of Microbiology, The Rockefeller University, New York, NY, USA

^* To whom correspondence should be addressed. Email: tomasz{at}rockefeller.edu.

Multidrug resistant strains of Staphylococcus aureus continue to increase in frequency worldwide – both in hospitals and in the community – raising serious problems for the chemotherapy of staphylococcal disease. Ceftobiprole (BAL9141) – renamed BPR – the active constituent of the prodrug ceftobiprole medocaril (BAL5788) is a new cephalosporin which was already shown to have powerful activity against a number of bacterial pathogens including S. aureus. In an effort to test possible limits to the antibacterial spectrum and efficacy of BPR, we examined the susceptibility of the relatively few pandemic MRSA clones that are responsible for the great majority of staphylococcal disease worldwide. We also included in the tests the highly oxacillin resistant subpopulations that are present with low frequencies in the cultures of these clones. Such subpopulations may represent a natural reservoir from which MRSA strains with decreased susceptibility to BPR may emerge in the future. We also tested the efficacy of BPR against MRSA with reduced susceptibility to vancomycin and against MRSA carrying the enterococcal vancomycin resistant gene complex. BPR was shown to be uniformly effective against all these resistant MRSA strains and the mechanism of superb antimicrobial activity correlated with the strikingly increased affinity of the cephalosporin against penicillin binding protein 2A (PBP2A) – the protein product of the antibiotic resistance determinant mecA.